1. Field of the Invention
The invention generally relates to processes for producing nucleoside derivatives.
2. Discussion of the Background
Dideoxynucleosides are expected to be useful in the field of medicaments because of their antiviral activity. Dideoxynucleosides are known compounds (for example, cf., H. Mitsuya and S. Broder, Proc. Natl. Acad. Soc. USA, vol. 93, 1911, 1986) Notably, 2',3'dideoxyinosine, with its antiviral activity, is expected to serve as an effective medicine.
2',3'-Didehydro-2',3'-dideoxy-5'-O-acylinosines are important intermediates for the synthesis of various compounds having pharmaceutical activity.
The following documents disclose synthetic methods available for making 2',3'-dideoxynucleosides from nucleoside starting materials:
(1) M. J. Robins et al, Tetrahedron Lett., 25, 367 (1984); PA1 (2) B. Samuelsson et al, Acta Chem. Scand., B36, 251 (1982); and PA1 (3) J. Chattopadhyaya et al, Acta Chem. Scand., B40, 251 (1982). PA1 X' is Cl, Br, or I; PA1 R' is H or a protective group which is readily removed; and PA1 R" is an acyl group. PA1 (1) the reaction proceeds in a high yield only when expensive reactants are used; PA1 (2) many products are produced; and PA1 (3) it is sometimes necessary to protect functional groups which do not take part in the reaction. PA1 (1) an acyl halide; or PA1 (2) an organic acid anhydride and a hydrogen halide in an organic solvent containing an organic acid to introduce an acyloxy group and a halogen atom at the 2'-position and 3'-position thereof (or at the 3'-position and 2'-position thereof)
The methods disclosed by these documents however employ adenosine or protected adenosine as the base material.
No method has yet been reported for producing 2',3'-dideoxynucleosides from inosine The main reason appears to be that no methods for the efficient removal of the zinc complex generated during such a process and which acts as a catalyst poison in the step of catalytic reduction are available.
In addition, 2',3'-didehydro-2',3'-dideoxyinosine derivatives tend;to decompose during catalytic reduction when a hydrous solvent is used as the reaction medium, and no method is available to prevent this decomposition.
2',3'-Dideoxynucleosides of formula (B): ##STR2## also have antiviral activity making them utilizable as drugs for treatment of, e.g., AIDS, etc. They can be used as medicaments (cf., Japanese Laid-Open Unexamined Patent Application No. 280500/1986 and J. Med. Chem., 30 440 (1987)). In formula (B), B represents a base known in nucleic acid chemistry such as a purine base bound to the sugar via its 9-position, a pyrimidine base bound to the sugar via its 1-position, etc.
A method for the production of 2',3'-dideoxynucleosides is known in which the compound: ##STR3## is reduced with hydrogen (H.sub.2) using a palladium catalyst in the presence of triethylamine. The protective group is then removed to obtain the following 2',3'-dideoxyadenosine: ##STR4## (cf., J. Am. Chem. Soc., 95, 4025 (1973)).
According to this method, the following 3'-deoxyadenosine: ##STR5## is produced in large quantities as an undesirable by-product, with formation ratios of the 2',3'-dideoxyadenosine to the 3'-deoxyadenosine reaching even 40:46. This method is consequently hardly advantageous from an industrial standpoint. Thus, a method for efficiently and selectively obtaining 2',3'-dideoxynucleosides using readily accessible starting materials at low cost is needed.
Some methods for preparing nucleoside derivatives, such as dideoxynucleosides, etc., using nucleosides as raw materials are known. Notably, nucleoside derivatives which are substituted at their 2'-position and 3'-position (or at their 3'-position and 2'-position thereof) by an acyloxy group and a halogen atom are important intermediates for preparing various substances showing pharmacological activities..
Compounds of formula (C) or formula (D) are important intermediates in these preparations: ##STR6## wherein: Base is a purine base or a pyrimidine base;
The compounds of formula (C) and formula (D) can be transformed into dideoxynucleosides by a known method which comprises reducing the compounds with hydrogen over a Pd/C catalyst and then, if necessary, subjecting the product to hydrolysis or ester exchange.
Known methods for preparing compounds of formula (C) or formula (D) include the following:
(1) The method of John G. Moffatt et al which comprises reacting nucleosides with 2-acetoxyisobutyric acid bromide ((1) J. Am. Chem. Soc., 95, 4025 (1973), (2) U.S. Pat. No. 3,658,787)).
(2) The method of Morris J. Robbins et al which comprises reacting 2',3'-O-(1-methoxyethylidene)nucleoside with pivalic acid chloride in the presence of sodium iodide (J. Am. Chem. Soc., 98, 8213 (1976)).
(3) The method of Engels et al which comprises reacting 2',3'-O-(1-ethoxyethylidene) adenosine derivatives with sodium iodide in the presence of a boron trifluoride-diethyl ether complex (Tetrahedron Letters, 21, 4339 (1980)).
(4) The method of John G. Moffatt et al which comprises reacting 2',3'-O-(1-ethoxyethylidene) adenosine with lithium bromide in acetonitrile, in the presence of a boron trifluoride-diethyl ether complex (J. Org. Chem., 39, 30 (1974)).
(5) The method of Colin B. Reese et al which comprises reacting 2',3'-O-(1-ethoxyethylidene) adenosine with acetyl bromide in dichloroethane (Synthesis, 304, 1983).
Although the above-described methods for preparing the important intermediates of formulae (C) and (D) are known, they can not be used industrially because they suffer the following problems:
If any of these preparation methods were to be considered for the industrial production of nucleoside derivatives such as dideoxynucleosides, etc., these problems would all dramatically raise the cost of producing these materials.
In view of the growing importance of 2',3'-dideoxynucleosides in treating viral diseases, there is thus a distinct need for (an) efficient process(es) for producing these materials, and for (a) process(es) capable of efficiently providing intermediates used to make 2',3'-dideoxynucleosides.